Experiments that address the effects of ethanol on human lymphocytes in vitro are described in this proposal. Preliminary data demonstrate that ethanol has significant effects on both interleukin-2-dependent proliferation of T lymphocytes and spontaneous natural killer cytotoxicity. In order to further investigate these findings, we shall examine both the short-term (hours-days) and long-term (weeks-months) consequences of ethanol exposure on a panel of human T cell clones. Clones are particularly advantageous for this study because they are homogeneous populations that are likely to produce clear-cut results, because their growth is regulated by antigen and achieved by a well-characterized hormonal system. Moreover, the panel includes clones with different phenotypes and functional attributes which will provide depth to our analysis, and results on the cloned populations will be complemented with studies of the effects of ethanol on peripheral blood mononuclear cells. Long- term studies of ethanol on lymphocytes will allow us to describe the effects of ethanol in terms of tolerance, dependence, adaptation, and reversibility. The stimulation of interleukin 2 receptor bearing cells by the soluble lymphokine involves a series of steps: binding of interleukin 2 to the high affinity receptor, internalization of the receptor-lymphokine complex, activation and membrane translocation of protein kinase C, and a decrease in adenylate cyclase activity. These events result in G(0) to G(1) transition, cellular enlargement, and eventual proliferation which have been shown to be inhibited by ethanol. We shall determine the effects to ethanol on the earlier events to identify the, locus of ethanol inhibition. Ethanol has profound effects on the cental nervous system; recent findings suggest that these effects can be accounted for by ethanol-mediated alterations of neurotransmitter systems. At the same time, functional analogues of many neuroreceptors have been found on lymphocytes. We propose to study the effects of ethanol on selected neuroreceptor analogues on lymphocytes. The results of experiments proposed here could enhance our understanding of the ethanol-mediated immunosuppression that accompanies ingestion of alcoholic beverages. Conversely, the use of ethanol to study T lymphocytes might also represent a tool for studying the physiology of T cells.